David L. Felten

Noradrenergic Sympathetic Neural Interactions with the Immune System: Structure and Function

Histochemical studies from our (Williams & Felten 1981, Williams et al. 1981, D. Felten et al. 1981, 1984, 1985, 1987a, 1987b, Livnat et al. 1985, Ackerman et al. 1986, S. Felten et al. 1987) and other laboratories (Giron et al. 1980, Bulloch & Pomeranz, 1984, Singh 1984, Walcott & MacLean 1985) have shown the presence of autonomic nerve fibers in specific compartments of both primary and secondary lymphoid organs. These nerve fibers are associated not only with blood vessels but also with lymphocytes and macrophages. We have demonstrated that the neurotransmitter norepinephrine (NE), present in the postganglionic sympathetic fibers that richly innervate lymphoid organs, acts in the spleen as both a paracrine secretion, available to receptors on cells in the white pulp, and a localized neurotransmitter in nerve terminals that directly contact T lymphocytes in the periarteriolar lymphatic sheath (PALS) (S. Felten et al. 1986, S. Felten & Olschowka 1987). We propose that NE in lymphoid organs fulfills the criteria for neurotransmission, estabUshed in more traditional efTector tissues such as the heart, and plays a role in the modulation of immune responses. This review summarizes evidence for neurotransmission, including presence and compartmentation of NE, transmitter release, post-synaptic receptors on cells of the immune system, and functional consequences of denervation and pharmacological manipulation of NE. We also review aspects of development, aging, and plasticity of noradrenergic (NA) fibers that enhance our understanding of their role in organs of the immune system.

Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems.

Sympathetic innervation was demonstrated in both perivascular and parenchymal regions of murine thymus and spleen. Catecholamine varicosities were associated with mast cells in these areas. The antibody response to sheep red blood cells of 7 week old mice that had been sympathectomized with six-hydroxydopamine (6OHDA) at birth was significantly elevated compared with saline treated controls. Alpha-methyl tyrosine (alpha-MT) and 6OHDA treatment of mice, producing a more complete sympathectomy, showed a significantly enhanced anti-SRBC response with respect to mice treated with alpha-MT or 6OHDA alone. Catecholamine levels in thymus, spleen, and adrenals of both experimental and control mice were measured using liquid chromatography with electrochemical detection (LCEC). The present study suggests that the sympathetic nervous system has a functional role in modulating the humoral immune response in vivo.

Evidence for a neurotrophic role of noradrenaline neurons in the postnatal development of rat cerebral cortex

SummaryThe effects of neonatal administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA; 1–4 doses of 100 mg/kg body weight s.c.) on the postnatal development of pyramidal neurons in several cortical regions of the rat was studied using a Golgi-Cox neuronal impregnation technique. Rats were sacrificed in the adult stage (eight weeks) and the following regions were studied: anterior frontal cortex, posterior frontal cortex (including motor cortex), anterior parietal cortex (including sensory cortex), posterior parieto-occipital cortex and cingulate cortex. Significant alterations were seen in animals which received four doses of 6-OHDA. These alterations can be summarized as follows: (1) a decreased length and branching of basolateral dendrites of pyramidal cells, with loss of dendritic spines, which were found in both the internal pyrimidal layer (layer V) and the external pyramidal layer (layer III), most abundantly in the frontal cortex and cingulate cortex; (2) an increased number of pyramidal cells of layer V with premature apical dendritic termination in layer III rather than the usual termination in layers I and II. This was most abundant in the cingulate cortex; (3) occasional disorientation of pyramidal cell apical dendrites away from the normal vertical plane by 15 or more degrees, seen in frontal, parietal and cingulate cortex; (4) an increased number of pyramidal cells with rounded somatic contours, found in frontal, anterior parietal and cingulate cortex. These phenomena were occasionally seen in normal cortex, but were significantly increased in their occurrence after four doses of 6-OHDA. Such alterations were not significant in rats treated with one or three doses of 6-OHDA. The extent and severity of morphological alterations correlate with reductions in endogenous noradrenaline (NA) in cerebral cortex, which was found to average 50% of control levels after one dose of 6-OHDA, an 80% reduction after three doses, and a 97–98% reduction after four doses, suggesting that the NA denervation must be almost complete to result in readily detectable significant morphological changes in the development of cortical pyramidal cells. No consistent changes in endogenous dopamine (DA) levels were observed, except for an increase in the cingulate cortex. The anatomical alterations in pyramidal cells described in the present study suggest that NA neurons which project into the cerebral cortex have a neurotrophic role in the postnatal development of cortex.

Innervation of Lymphoid Tissue

Publisher Summary This chapter focuses on the location of nerves within organs of the immune system and the possible association of these nerves with specific compartments or cellular regions. It also focuses on neurotransmitters in these nerves, which act as signal molecules within the immune system. Lymphoid organs are composed of a reticular stroma that forms a meshwork that provides support for varying populations of cells of the immune system, many of which are mobile cells. Secondary lymphoid organs and accumulations have T-dependent areas and B-dependent areas. It is much more common to find innervation, whether noradrenergic or peptidergic, associated with the T-dependent areas. However, occasional fibers do seem to enter the follicles. There are also areas where T lymphocytes, B lymphocytes, macrophages, and other cells are mixed; these areas often are associated with large blood or lymph sinuses, where antigen presentation takes place, such as the marginal zone of the spleen and the medullary cords of the lymph nodes. These areas also are innervated largely by noradrenergic/NPY-containing fibers.

Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults ☆

Parkinsons disease is a neurodegenerative disorder characterized mainly by damage to the dopaminergic nigrostriatal system. Recently, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce damage in the nigrostriatal system, accompanied by Parkinson-like symptoms in humans. We present here evidence that MPTP treatment in aged 21-month-old mice produced a marked reduction in the presence and intensity of fluorescence in noradrenergic neurons of the locus coeruleus and in dopaminergic neurons of the ventral tegmental area in addition to extensive damage to the substantia nigra. Aged mice treated with MPTP also showed physical signs of movement disability characterized by marked akinesia, rigidity of the hind limbs, and an initial resting tremor of the entire body. Such symptoms were less evident in young mice treated with MPTP. These remarkable initial behavioral effects of MPTP treatment in aged mice and evidence of reduced catecholamine fluorescence in the locus coeruleus and ventral tegmental area suggest that aged mice are more sensitive to, and more severely affected by MPTP treatment than young mice. We suggest that these MPTP-treated aged mice provide a useful animal model for studying both anatomical and functional characteristics of Parkinsons disease.

Long-term effect of MPTP in the mouse brain in relation to aging: neurochemical and immunocytochemical analysis

The long-term effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central monoaminergic neurons in young (2-3 months) and aging (12 months) C57BL/6 mice has been studied using neurochemical and immunocytochemical techniques. MPTP treatment (4 x 20 mg/kg i.p. given 12 h apart) resulted in significant depletion of dopamine (DA) concentration in the striatum, substantia nigra, nucleus accumbens, and olfactory tubercle 1 week after treatment in both young and aging mice. Although a decreased DA concentration in the ventral tegmental area was not seen in young mice, aging mice did show a significant decrease. The extent of decrease of DA concentration was greater in aging mice than in young mice in all areas investigated except in dorsal striatum. The long-term effect of MPTP on DA neurons in young mice included considerable recovery of DA concentration in both nigrostriatal and mesolimbic DA systems following the initial profound depletion; such recovery was minimal in aging mice, even 3 months after MPTP treatment. In young mice treated with MPTP, no significant change of norepinephrine (NE) or serotonin (5-HT) concentration was observed in any area investigated while a significant decrease of NE and 5-HT concentration was seen in several brain areas investigated in aging mice. Immunocytochemical analysis revealed that the MPTP injection resulted in marked disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in striatum of both young and aging mice 1 week following treatment. Partial recovery of TH-IR fibers was seen 5 weeks or 3 months after MPTP treatment in young mice, while no such apparent recovery was seen in aging mice. Aging mice also showed significant decrease in the number of TH-positive cell bodies in the substantia nigra and ventral tegmental area through all periods investigated, while such a significant decrease was only seen in the substantia nigra of young mice 1 week after treatment. We conclude that aging mice are more sensitive to MPTP and show more widespread damage to the monoaminergic systems than young mice, suggesting that MPTP-treated aging mice provide a more useful model for studying anatomical and neurochemical characteristics of Parkinsons disease than young mice.

Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy

Chemical sympathectomy of adult mice with 6-hydroxydopamine (6-OHDA) either prior to or following epicutaneous sensitization with the trinitrophenyl (TNP) hapten decreased the delayed hypersensitivity (DH) response to ear challenge. To determine if uptake of 6-OHDA into sympathetic nerve terminals, and their subsequent destruction, was required for suppression of DH, the catecholamine uptake blocker, desipramine, was employed to block 6-OHDA-induced sympathetic denervation. Pretreatment with desipramine prevented the depression of DH. In vivo treatment with the beta blocker, propranolol, did not alter the 6-OHDA effect, eliminating the potential contribution of released catecholamines, acting on beta-adrenoceptors, to DH reduction. Sympathectomy before sensitization also diminished hapten-specific T cell reactivity of sensitized lymph node (LN) cells, as measured in vitro by IL-2 production and CTL generation. In vivo DNA synthesis in draining LN in response to immunization was modestly decreased following 6-OHDA. Thus, sympathetic denervation appears to impair T cell activity in vivo and in vitro. Overall, these results indicate the SNS plays a role in generation of cell-mediated immunity.

MPTP-treated young mice but not aging mice show partial recovery of the nigrostriatal dopaminergic system by stereotaxic injection of acidic fibroblast growth factor (aFGF)

Acidic fibroblast growth factor (aFGF) is a heparin-binding polypeptide that acts as a neurotrophic factor for certain central and peripheral neurons. Acidic FGF was injected stereotaxically into the striatum of young (2-month-old) and aging (12-month-old) C57BL/6 mice that were treated 1 week before with systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment (4 x 20 mg/kg, i.p. given 12 h apart) reduced tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in the striatum and reduced dopamine (DA) concentration to 32% of the controls in young and 20% of the controls in aging mouse brain 5 weeks after administration. Although the DA concentration recovered to 43% of the controls in young mice following stereotaxic injection of aFGF 5 weeks after MPTP treatment, aging mice with such treatment did not show a significant recovery of DA concentration. Computerized image analysis of TH-IR fibers in the striatum also showed significant recovery in young mice treated with aFGF, while aging mice did not show a significant recovery. We conclude that treatment of MPTP-depleted young mice with aFGF results in partial recovery in the nigrostriatal DA system but such benefits decline with age.

Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats

Pergolide, a potent D2 presynaptic agonist with postsynaptic D2 agonist activity and some D1 agonist activity was administered in the diet (0.5 mg/kg/day) of male Fischer 344 rats from age 3 to age 26 months. We hypothesized that the potent D2 presynaptic activity would reduce the baseline release of dopamine (DA) and thereby slow the formation of toxic oxidative metabolites that lead to age-related deterioration of nigrostriatal DA neurons. Pair-fed rats served as controls. We observed age-related losses of fluorescent DA cell bodies in the substantia nigra pars compacta and of fluorescent DA terminals in the striatum; chronic pergolide administration prevented these losses. Pergolide administration also prevented the age-related diminution of DA fluorescence intensity in substantia nigra cell bodies. A large decline in 3H-DA uptake with age was partially prevented by pergolide administration. We found no age-related alteration in the concentration of DA in the striatum and pergolide did not alter this concentration. Pergolide treatment resulted in only minor alterations in striatal 3H-spiperone binding and no change in dendritic arborizations of either DA substantia nigra neurons or medium spiny striatal neurons. Pergolide administration also prevented an age-related decline in circulating FSH levels. The uptake data and quantitative morphological findings suggest that pergolide administration in the diet for 2 years exerts a protective effect on age-related deterioration of DA nigrostriatal neurons. This finding was consistent with clinical reports of a subset of patients with Parkinsons disease in whom long-term efficacy of pergolide therapy is observed.

Sympathetic innervation of lymph nodes in mice

Noradrenergic innervation of popliteal and mesenteric lymph nodes in mice was examined with fluorescence histochemistry. Dense varicose plexuses entered the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region. Fine, delicate varicosities and small vascular plexuses continued into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes. A subcapsular plexus contributed fibers into the cortical and paracortical regions. Chemical measurements revealed the presence of norepinephrine in lymph nodes that was depletable with 6-hydroxydopamine. Depletion of norepinephrine from lymph nodes with this agent resulted in a diminished primary immune response in draining lymph nodes following subcutaneous injection of an antigen in two mouse strains, but had no effect in two other strains. These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs.